Systemic Innate Immune Responses in Secondary Syphilis

描述(申请人提供)：性梅毒是一种由螺旋体病原体梅毒螺旋体引起的性传播疾病。这种疾病仍然没有得到控制，特别是在资源稀缺的地区，在那里并不总是可以获得检测、治疗和适当的后续行动。梅毒的特点是在最初感染的地方出现局部溃疡，表现为一系列慢性全身炎症表现，如果不治疗，可能会导致严重的并发症，甚至死亡。无法培养这种细菌阻碍了充分了解其发病机制的努力，特别是为什么螺旋体能够逃避免疫系统。因此，这里提出的研究旨在更好地描述这种免疫反应的性质，因为它发生在人类梅毒中。二期梅毒患者的全身性细胞天然免疫反应将是当前提案的重点。我们推测，在二期梅毒中，血液中梅毒螺旋体的存在直接激活了循环中的单核细胞和树突状细胞。为此，在特定的目标1中，我们将首先使用一种新的实时定量PCR方法证实二期梅毒患者的血液中存在螺旋体DNA，在特定的目标2中，我们将通过多参数四色流式细胞术和实时定量聚合酶链式反应(RT-PCR)来表征循环单核细胞和树突状细胞中梅毒螺旋体诱导的免疫反应，以定量其促炎细胞因子的基因表达信号。补充的体外研究，旨在确定细菌对天然免疫细胞和获得性免疫细胞的特定成分的影响。通过这两条平行线的研究，我们将对梅毒的发病机制有一个更深入的了解，这可以从细胞和分子的角度进一步发展，最终促进疫苗的开发。与Fogarty国际中心缩小各国健康差距的使命相一致，计划开展的活动还将：(1)支持USPI和哥伦比亚卡利的FC之间的梅毒免疫生物学合作研究；(2)加强外国研究所(CIDEIM)、研究能力和技术基础；(3)促进两个设在美国的机构(UCHC和CCMC)与CIDEIM之间持续和富有成效的研究；以及(4)提供哥伦比亚该地区有关性病梅毒的必要流行病学数据。

DESCRIPTION (provided by applicant): Venereal syphilis is a sexually transmitted disease caused by the spirochetal pathogen, Treponema pallidum. The disease remains uncontrolled, particularly in resource-scarce regions where testing, treatment and proper follow-up are not always accessible. Syphilis is characterized by the appearance of a local ulcer at the site of initial infection to an array of chronic systemic inflammatory manifestations that when left untreated, can cause severe complications and even death. The inability to culture the bacterium has hampered efforts to fully understand its pathogenesis, particularly why the spirochete is able to evade the immune system. The research proposed here is thus designed to better characterize the nature this immune response as it occurs in human syphilis. The systemic cellular innate immune response in secondary syphilis patients will be the focus of the current proposal. We hypothesize that in secondary syphilis, the presence of T. pallidum in the blood directly activates circulating monocytes and dendritic cells. To do so, in Specific Aim 1 we will first confirm that spirochetal DNA is present in blood from secondary syphilis patients using a novel Real Time Quantitative PCR method and in Specific Aim 2 we will characterize T. pallidum driven immune responses in circulating monocytes and dendritic cells by using multiparameter four color flow cytometry and `real time' PCR (RT-PCR) to quantify their pro- inflammatory cytokine gene expression signals. Complementary ex vivo studies, are structured to identify the effect of the bacterium on specific components of innate and adaptive immune cells. From these two parallel lines of research, we will obtain a more mechanistic understanding of the pathogenesis of syphilis, which can be further developed along cellular and molecular lines and ultimately facilitate development of a vaccine. In concert with the Fogarty International Center's mission to reduce health disparities amongst nations, the planned activities will also: (1) support collaborative syphilis immunobiology research between the USPI and the FC in Cali, Colombia; (2) strengthen the foreign institute's (CIDEIM), research capabilities and technical base; (3) foster sustained and productive research between two US based institutions (UCHC and CCMC) and CIDEIM; and (4) provide needed epidemiological data about venereal syphilis for that region of Colombia.